Process for the production of piperidine derivatives

ABSTRACT

The present invention relates to processes for preparing certain piperidine derivatives, including fexofenadine (F), the active ingredient in the non-sedating antihistamine sold in the U.S. under the designation “Allegra®”. This invention also relates to novel synthetic intermediates useful in the processes of the present invention.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to processes for preparing certainpiperidine derivatives, including fexofenadine (F), the activeingredient in the non-sedating antihistamine sold in the U.S. under thedesignation “Allegra®”. This invention also relates to novel syntheticintermediates useful in the processes of the present invention.

SUMMARY OF THE INVENTION

[0002] The present invention relates to processes for the preparation ofpiperidine derivatives of the formulas I, II, VI and VII:

[0003] wherein

[0004] n is 0 or1;

[0005] R1 is hydrogen or hydroxy;

[0006] R2 is hydrogen;

[0007] R1 and R2 taken together form a double bond between the carbonatoms bearing R1 and R2;

[0008] R3 is COOH, CO₂alkyl, CH₂OH, hydroxyl, protected hydroxyl, cyano,CONH₂, CONHalkyl or CON(alkyl)₂, wherein each of the alkyl groupscontained in any of them contains from 1-6 carbon atoms

[0009] A, B, and D may be substituents of their respective rings in themeta, para or ortho position and which may be different or the same andare hydrogen, halogens, alkyl, hydroxy, or alkoxy,

[0010] and pharmaceutically acceptable salts thereof,

[0011] with the proviso that where R1 and R2 are taken together to forma double bond between the carbon atoms bearing R1 and R2 or where R1 ishydroxy, n is 0.

[0012] The present invention also relates to novel syntheticintermediates for formulas III and IIIa, and VI which are useful in thepreparation of the piperidine derivatives of formulas I, II, VI and VII:

[0013] wherein A, B, D, R1, R2, R3 and n are as previously defined andX⁺ is a Lewis Acid.

[0014] Although a wide variety of piperidine derivatives can be preparedby the process of the present invention, it is particularly useful forpreparing fexofenadine (F), the active ingredient in the non-sedatingantihistamine sold in the U.S. under the designation “Allegra®”:

[0015] Thus, particularly preferred novel synthetic intermediates foruse in the processes of the present invention which are useful in thepreparation of the fexofenadine (F) are compounds of the formulas VIII,VIIIa, and IX:

[0016] wherein alkyl is 1-6 carbon atoms and X⁺ is a Lewis acid.

[0017] The processes of the present invention for the preparation ofpiperidine derivatives of the formulas I, II, VI and VII comprise:

[0018] a) acylating a starting compound of the formula 19:

[0019] with a compound of the formula 18:

[0020] under conditions effective to produce a mixture of regioisomersof the formula XI:

[0021] b) recovering from the mixture of regioisomers the compound ofthe formula III:

[0022] c) converting the compound of step b) to the piperidinederivative compound of the formula VI:

[0023] with a piperidine compound of the formula 17:

[0024] d) optionally reducing the piperidine derivative compound of stepc) to give the compound of the formula I:

[0025] e) optionally reducing the piperidine derivative compound of stepc) to give the piperidine derivative of the formula VII;

[0026] and

[0027] f) optionally oxidizing the piperidine derivative of step d togive the piperidine derivative of formula II:

[0028] wherein all substituents are as previously defined.

[0029] Included within this process is a process for preparation offexofenadine (F), the active ingredient in the non-sedatingantihistamine sold in the U.S. under the designation “Allegra®”, whichcomprises:

[0030] a) acylating a starting compound of the formula 21:

[0031] with a compound of the formula 20:

[0032] under conditions effective to produce a mixture of regioisomersof the formula 25:

[0033] b) recovering from the mixture of regioisomers the compound ofthe formula VIII:

[0034] c) converting the compound of step b) to the piperidinederivative compound of the formula IX:

[0035] with a piperidine compound of the formula 23:

[0036] d) reducing the piperidine derivative compound of step c) toprovide a piperidine derivative of the formula 24;

[0037] and

[0038] e) converting the CO₂alkyl moiety of the piperidine derivative offormula 24 to a CO₂H moiety to produce fexofenadine (F)

[0039] wherein alkyl is 1-6 carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION

[0040] The present invention relates to a process for the preparation ofpiperidine derivatives of the formulas I, II, VI and VII:

[0041] wherein

[0042] n is 0 or 1;

[0043] R1 is hydrogen or hydroxy;

[0044] R2 is hydrogen;

[0045] R1 and R2 taken together form a double bond between the carbonatoms bearing R1 and R2;

[0046] R3 is COOH, CO₂alkyl, CH₂OH, hydroxyl, protected hydroxyl, cyano,CONH₂, CONHalkyl or CON(alkyl)₂, wherein each of the alkyl groupscontained in any of them contains from 1-6 carbon atoms

[0047] A, B, and D may be substituents of their respective rings in themeta, para or ortho position and which may be different or the same andare hydrogen, halogens, alkyl, hydroxy, or alkoxy,

[0048] and pharmaceutically acceptable salts thereof,

[0049] with the proviso that where R1 and R2 are taken together to forma double bond between the carbon atoms bearing R1 and R2 or where R1 ishydroxy, n is 0.

[0050] The present invention also relates to novel intermediates of theformula III, IIIa, and VI:

[0051] wherein A, B, D, R1, R2, R3 and n are as previously defined andX⁺ is a Lewis Acid.

[0052] Although a wide variety of piperidine derivatives can be preparedby the process of the present invention, it is particularly useful forpreparing fexofenadine (F), the active ingredient in the non-sedatingantihistamine sold in the U.S. under the designation “Allegra®”:

[0053] Thus, particularly preferred novel synthetic intermediates foruse in the processes of the present invention which are useful in thepreparation of the fexofenadine (F) are compounds of the formulas VIII,VIIIa, and IX:

[0054] wherein alkyl is 1-6 carbon atoms and X⁺ is a Lewis Acid.

[0055] The processes of the present invention for the preparation ofpiperidine derivatives of the formulas I, II, VI and VII comprise:

[0056] a) acylating a starting compound of the formula 19:

[0057] with a compound of the formula 18:

[0058] under conditions effective to produce a mixture of regioisomersof the formula XI:

[0059] b) recovering from the mixture of regioisomers the compound ofthe formula III:

[0060] c) converting the compound of step b) to the piperidinederivative compound of the formula VI:

[0061] with a piperidine compound of the formula 17:

[0062] d) optionally reducing the piperidine derivative compound of stepc) to give the compound of the formula I:

[0063] e) optionally reducing the piperidine derivative compound of stepc) to give the piperidine derivative of the formula VII;

[0064] and

[0065] f) optionally oxidizing the piperidine derivative of step d togive the piperidine derivative of formula II:

[0066] wherein all substituents are as previously defined.

[0067] Included within this process is a process for preparation offexofenadine (F), the active ingredient in the non-sedatingantihistamine sold in the U.S. under the designation “Allegra®”, whichcomprises:

[0068] a) acylating a starting compound of the formula 21:

[0069] with a compound of the formula 18:

[0070] under conditions effective to produce a mixture of regioisomersof the formula 25:

[0071] b) recovering from the mixture of regioisomers the compound ofthe formula VIII:

[0072] c) converting the compound of step b) to the piperidinederivative compound of the formula IX:

[0073] with a piperidine compound of the formula 23:

[0074] d) reducing the piperidine derivative compound of step c) toprovide the piperidine derivative of formula 24; and

[0075] e) converting the CO₂alkyl moiety on the piperidine derivative offormula 24 to a CO₂H moiety to produce fexofenadine (F)

[0076] wherein alkyl is 1-6 carbon atoms.

[0077] This novel process for preparing the piperidine derivatives offormulas I, II, VI and VII and novel intermediates III, IIIa, and VIwhich are useful for preparing piperidine derivatives of formulas I, II,VI, and VII is outlined in Scheme A. In Scheme A, all substituents areas previously defined unless otherwise indicated.

[0078] Scheme A provides general synthetic procedures for preparing thepiperidine derivatives of formulas I, II, VI and VII and novelintermediates III IIIa, and VI useful for preparing piperidinederivatives of formulas I, II, VI, and VII.

[0079] In step a, a starting compound of formula (19) is acylated with adibasic acid anhydride of formula (18) under standard Friedel-Craftsconditions well known in the art, to produce a first mixture ofregioisomers of formula XI, typically in a ratio of about 60% para, 40%meta isomers. Conditions for the acylation reaction of step a are thoseconventionally used in the Friedel-Crafts acylation reactions. Examplesof compounds of formula (18) are substituted succinic anhydrides,glutaric anhydride, substituted glutaric anhydrides, polymericanhydrides of higher dibasic acids, maleic anhydride, or substitutedmaleic anhydride.

[0080] For example, the acylation reaction of step a is catalyzed by aLewis acid, such as AlCl₃, in an anhydrous aprotic solvent such ascarbon disulfide, tetrachloethane, methylene chloride, nitrobenzene, ora mixture of anhydrous aprotic solvents. The reaction is typicallycarried out for a period of about 1 to about 18 hours, with about 12 toabout 18 hours being preferred, at a temperature of about 0° C. to aboutthe reflux temperature of the solvent utilized, with about 0° C. toabout 25° C. being preferred.

[0081] In step b1, step b2, and step b3, the compound of formula III isrecovered from the first mixture of regioisomers of formula XI. Suchrecovery is carried out by first, in step b1, forming the second mixtureof regioisomeric salts of formula XIa:

[0082] wherein X⁺ is a Lewis acid and R3 and A are as previouslydefined; second, in step b2, crystallizing from the second mixture ofregioisomeric salts of formula X1a, the salt of formula IIIa:

[0083] wherein X⁺ is a Lewis acid and A and R3 is as previously defined.Such crystallization is carried out by fractional crystallizationtechniques known in the art. Suitable solvents for fractionalcrystallization include: alcohol solvents, like methanol, ethanol,isopropyl alcohol; ketone solvents, such as acetone or methyl ethylketone; ester containing solvents, like ethyl acetate or isopropylacetate; ethereal solvents, like tetrahydrofuran; and acetonitrile. Thepreferred solvent is isopropyl alcohol. Suitable salts for fractionalcrystallization include alkali metal salts or preferably ammonium saltsof the form NR₁₀R₁₁R₁₂, where R₁₀, R₁₁, and R₁₂ are hydrogen or astraight or branched alkyl of 1 to 6 carbon atoms which may besubstituted at any position with a phenyl ring or a substituted phenylring. Of the salts of this form, phenethylamine is preferred. The pureregioisomer is isolated by filtration and in step b3, is converted tothe free acid to give the compound of formula III by procedures wellknown in the art. Typically, this conversion is done by the treatmentwith acid.

[0084] In step c, the compound of formula III is coupled to a piperidinederivative of formula 17 under conditions effective to form thepiperidine derivatives of formula VI. Such couplings are well known inthe art. Generally, such procedures involve activating the free carboxylgroup with reagents such as 1,3-dicyclohexylcarbodimide (DCC),2-chloro4,6-dimethoxy-1,3,5-triazine (CDMT), paranitrophenol, or as theacid chloride or mixed anhydride followed by addition of a primary orsecondary amine. These reactions are carried out in an anhydrous aproticsolvent such as, ethyl acetate, methylene chloride, tetrahydrofuran ordimethylformamide with the preferred solvent being tetrahydrofuran. Thereaction is typically carried out for a time of about 0.5 to about 12hours, with about 2 to about 12 hours being preferred, at a temperatureof about 0° C. to about the reflux temperature of the solvent utilized,with about 0° C. to about 25° C. being preferred.

[0085] In optional step d, the amido and keto moieties of the piperidinederivative of formula VI are reduced to give the piperidine derivativeof formula I. Reduction can be carried out with the borane complexessuch as, borane-methyl sulfide, borane-tetrahydrofuran in a suitablesolvent. Alternatively, if the optically active derivative is desired,asymmetric reduction may be performed by addition of the appropriatecatalyst such as, oxaborolidine based catalysts. The reduction iscarried out in an anhydrous aprotic solvent, such as tetrahydrofuran ordioxane. The preferred solvent is tetrahydrofuran. The reduction istypically carried out at a temperature of from about 25° C. to about thereflux temperature of the solvent. Typical reaction times are from about0.5 hours to about 48 hours, with about 12 to about 48 hours beingpreferred. The amino-borane complexes formed during reduction with theborane complexes are well known in the art and are typically broken byreaction of the complex with acid or by addition of TMEDA(N,N,N′,N′-tetramethylethylenediamine) to the complex in ether, orthrough heating in protic media. This reaction is carried out in alcoholsolvents, like methanol, ethanol, isopropyl alcohoThe preferred solventis ethanol The reaction is carried out at a temperature ranging from 25°C. to the reflux temperature of the solvent and a reaction time of about0.5 to about 24 hours, with about 12 to about 24 hours being preferred.

[0086] In optional step e, the keto moiety of the piperidine derivativeof formula VI can be selectively reduced without affecting the amidemoiety to give the piperidine derivative of formula VII. The selectivereduction is typically done with sodium borohydride in lower alcoholsolvents such as, methanol, ethanol, or isopropyl alcohol. The reactionis carried out at a temperature range of about 25° C. to about thereflux temperature of the solvent. Reaction times are typically about0.5 hours to about 12 hours.

[0087] In optional step f, the hydroxy moiety of the piperidinederivative of formula I is oxidized to give the piperidine derivative offormula II.

[0088] This novel process as applied to the preparation of fexofenadine(F), the active ingredient in the non-sedating antihistamine sold in theU.S. under the designation “Allegra®” and novel intermediates VIII,VIIIa, and IX is outlined in Scheme B. In Scheme B, all substituents areas previously defined unless otherwise indicated.

[0089] Scheme B provides a general synthetic procedure for preparingfexofenadine (F), the active ingredient in the non-sedatingantihistamine sold in the U.S. under the designation “Allegra®” andnovel intermediates VIII, VIIIa, and IX.

[0090] In step a, a starting compound of formula (21) is acylated with asuccinic anhydride of formula (18) under standard Friedel-Craftsconditions well known in the art, to produce a first mixture ofregioisomers of formula 25, typically in a ratio of about 60% para, 40%meta isomers. Conditions for the acylation reaction of step a are thoseconventionally used in the Friedel-Crafts acylation reactions.

[0091] For example, the acylation reaction of step a is catalyzed by aLewis acid, such as AlCl₃, in an anhydrous aprotic solvent such ascarbon disulfide, tetrachloroethane, methylene chloride, nitrobenzene,or a mixture of anhydrous aprotic solvents. The reaction is typicallycarried out for a period of about 1 to about 18 hours, with about 2 toabout 18 hours being preferred, at a temperature of about 0° C. to aboutthe reflux temperature of the solvent utilized, with about 0° C. toabout 25° C. being preferred.

[0092] In step b1, step b2 and step b3, the compound of formula VIII isrecovered from the first mixture of regioisomers of formula 25. Suchrecovery is carried out by first, in step b1, forming the second mixtureof regioisomeric salts of formula 25a;

[0093] wherein X⁺ is a Lewis acid and alkyl is as previously defined;second, in step b2, crystallizing from the second mixture ofregioisomeric salts of formula 25a, the salt of formula VIIIa:

[0094] wherein X⁺ is a Lewis acid and alkyl is as previously defined.Such crystallization is carried out by fractional crystallizationtechniques known in the art. Suitable solvents for fractionalcrystallization include: alcohol solvents, like methanol, ethanol,isopropyl alcohol; ketone solvents, such as acetone or methyl ethylketone; ester containing solvents, like ethyl acetate or isopropylacetate; ethereal solvents, like tetrahydrofuran; and acetonitrile. Thepreferred solvent is isopropyl alcohol. Suitable salts for fractionalcrystallization include alkali metal salts or preferably ammonium saltsof the form NR₁₀R₁₁R₁₂, where R₁₀, R₁₁, and R₁₂ are hydrogen or astraight or branched alkyl of 1 to 6 carbon atoms which may besubstituted at any position with a phenyl ring or a substituted phenylring. Of the salts of this form, phenethylamine is preferred, providingcompounds of the formula 25a′ after step b1 and compound of the formulaVIIIa′ after step b2:

[0095] The pure regioisomer is isolated by filtration and in step b3, isconverted to the free acid to give the compound of formula VIII byprocedures well known in the art. Typically, this conversion is done bythe treatment with acid.

[0096] In step c, the compound of formula VIII is coupled to apiperidine derivative of formula 23 under conditions effective to formthe piperidine derivatives of formula IX. Such couplings are well knownin the art. Generally, such procedures involve activating the freecarboxyl group with reagents such as 1,3-dicyclohexylcarbodimide (DCC),2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), paranitrophenol, or as theacid chloride or mixed anhydride followed by addition of a primary orsecondary amine. These reactions are carried out in an anhydrous aproticsolvent such as, ethyl acetate, methylene chloride, tetrahydrofuran ordimethylformamide with the preferred solvent being tetrahydrofuran. Thereaction is typically carried out for a time of about 0.5 to about 12hours, with about 2 to about 12 hours being preferred, at a temperatureof about 0° C. to about the reflux temperature of the solvent utilized,with about 0° C. to about 25° C. being preferred.

[0097] In step d, the amido and keto moieties of the piperidinederivative of formula IX are reduced to give the piperidine derivativeof formula 24. Reduction can be carried out with the borane complexessuch as, borane-methyl sulfide, borane-tetrahydrofuran in a suitablesolvent. Alternatively, if the optically active derivative is desired,asymmetric reduction may be performed by addition of the appropriatecatalyst such as, oxaborolidine based catalysts. The reduction iscarried out in an anhydrous aprotic solvent, such as tetrahydrofuran ordioxane. The preferred solvent is tetrahydrofuran. The reduction istypically carried out at a temperature of from about 25° C. to about thereflux temperature of the solvent. Typical reaction times are from about0.5 to about 48 hours, with about 12 hours to about 48 hours beingpreferred. The amino-borane complexes formed during reduction with theborane complexes are well known in the art and are typically broken byreaction of the complex with acid, by addition of TMEDA(N,N,N′,N′-tetramethylethylenediamine) to the complex in ether, orthrough heating in protic media This reaction is carried out in alcoholsolvents, like methanol, ethanol, isopropyl alcohol The preferredsolvent is ethanol. The reaction is carried out at a temperature rangingfrom 25° C. to the reflux temperature of the solvent and a reaction timeof about 0.5 to about 24 hours, with about 12 to about 24 hours beingpreferred.

[0098] In step e, the ester moiety of the piperidine derivative offormula 24 is converted to the carboxylic acid by techniques andprocedures well known to those in the art to give fexofenadine (F). Forexample, the ester moiety may be hydrolyzed using a suitablenon-nucleophilic base, such as sodium methoxide in methanol as is knownin the art. Other methods known in the art for ester cleavage includepotassium carbonate in methanol, methanolic ammonia, potassiumcarbonate, potassium hydroxide, calcium hydroxide, sodium hydroxide,magnesium hydroxide, sodium hydroxide/pyridine in methanol, potassiumcyanide in ethanol and sodium hydroxide in aqueous alcohols, withpotassium hydroxide being preferred. The reaction is typically carriedout in an aqueous lower alcohol solvent, such as methanol, ethanol,isopropyl alcohol, n-butanol, 2-ethoxyethanol or ethylene glycol orpyridine, at temperatures ranging from about room temperature to aboutthe reflux temperature of the solvent, and the reaction time varies fromabout ½ hour to about 100 hours.

[0099] The following examples present typical syntheses as described inSchemes A and B. These examples are understood to be illustrative onlyand are not intended to limit the scope of the present invention in anyway. As used herein, the following terms have the indicated meanings:“g” refers to grams; “mmol” refers to millimols; “mL” refers tomilliliters; “bp” refers to boiling point; “mp” refers to melting point;“°C.” refers to degrees Celsius; “mm Hg” refers to millimeters ofmercury; “μL” refers to microliters; “μg” refers to micrograms; and “μM”refers to micromolar.

EXAMPLE 1 Scheme B step a: Preparation of4-[4-(1-Methoxycarbonyl-1-methyl-ethyl)-phenyl-]4-oxo-butyric acid andof 4-[3-(1-Methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acid(25)

[0100] Method 1:

[0101] Aluminum chloride (144g, 1.08 moles) was added to 200 mL ofcarbon disulfide in a 1 L reaction kettle with stirring under a nitrogenatmosphere. The mixture was chilled to 0° C. to 5° C. after which timesuccinic anhydride (20) (26.0 g, 0.260 moles) was added in one portion.α,α-Dimethylphenylacetic acid methyl ester (21) (40.0 g, 0.224 moles)was added dropwise over 20 minutes to the reaction mixture. Afteraddition, the ice-bath was removed and the mixture was allowed to warmto ambient temperature. After 2.75 hours, the carbon disulfide wasdecanted and discarded. The firm reaction product was placed(portionwise) into concentrated hydrochloric acid (150 mL) and crushedice (1000 g). The product was extracted with ethyl acetate (2×400 mL)and washed with water (2×300 mL), brine (1×300 mL). The organic layerwas dried over anhydrous magnesium sulfate, filtered and the ethylacetate removed in vacuo to give a 60:40 (para:meta) mixture of thetitle compounds (25) as a light yellow oil.

[0102] Method 2:

[0103] Add succinic anhydride (20) (2 g, 0.050 moles) to a stirredsolution of anhydrous methylene chloride (25 mL) and nitrobenzene (5 mL)under a nitrogen atmosphere. The reaction mixture was chilled to 0°C.-5° C. and aluminum chloride (20 g, 0.150 moles) was added in 5 gincrements over 30 minutes. α,α-Dimethylphenylacetic acid methyl ester(21) (5.6 g, 0.031 moles) was added dropwise over 20 minutes to thereaction mixture. After 4 hours, the ice bath was removed and thereaction was allowed to proceed at room temperature for 16 hours. Thereaction was quenched by slowly pouring into concentrated hydrochloricacid (50 mL) and crushed ice (300 g). Ethyl acetate (400 mL) was addedwith stirring. The organic phases were separated and washed with dilutebrine (3×300 mL). The product was removed from the organic by extractionwith saturated aqueous sodium bicarbonate (2×100 mL) containing brine(50 mL). The aqueous layer was acidified by slowly pouring intoconcentrated hydrochloric acid (50 ml) and ice (300 g). The product wasrecovered from the acidified reaction with ethyl acetate (200 mL). Theorganics were washed with water (400 mL), brine (100 mL), and dried overanhydrous sodium sulfate. Removal of the solvent in vacuo gave the titlecompounds (25) as a yellow oil (4.5 g, 0.016 moles), 80.4% yield.

[0104] Method 3:

[0105] Add succinic anhydride (16 g, 0.0160 moles ) to anhydrous carbondisulfide (110 mL) with stirring under a nitrogen atmosphere. Thereaction mixture was chilled to 0° C. -5° C. and aluminum chloride (72g, 0.540 moles) was added in 18 g increments over 30 minutes.α,α-Dimethylphenylacetic acid methyl ester (21) (19.7 g, 0.111 moles)was added dropwise to the reaction mixture over 30 minutes. After 4hours, the carbon disulfide was decanted from the insoluble reactionproduct, which was removed and carefully decomposed with concentratedhydrochloric acid (100 mL) and crushed ice (500 g). Ethyl acetate (600mL) was added with stirring. The organic phases were separated andwashed with dilute brine (3×400 mL). The product was removed as itssodium salt from the organic by extraction with saturated aqueous sodiumbicarbonate (2×200 mL) containing brine (50 mL). The aqueous layer wasacidified by slowly pouring into concentrated hydrochloric acid (100 mL)and ice (600 g). The product was recovered from the acidified reactionwith ethyl acetate (300 mL). The organics were washed with water (2×300mL), brine (200 mL), and dried over anhydrous sodium sulfate. Removal ofthe solvent in vacuo gave the title compounds (25) as a clear oil (22 g,0.079 moles), 71.2% yield.

EXAMPLE 2 Scheme B. step b1: Preparation of4-[4-(1-Methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acidphenethylamine salt and of4-[3-(1-Methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acidphenethylamine salt (25a′)

[0106] Method 1:

[0107] The mixture of4-[4-(1-methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acid andof 4-[3-(1-methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acid(25) from Example 1, Method 1 is dissolved in 150 mL of diethyl etherand cooled to 50° C. To the solution (assume 100% yield, 62.5 g, 0.224moles) was added phenethylamine (28.5 g, 29.5 mL, 0.235 moles, 1.05 eq.)dropwise over 10 minutes. The suspension is placed in the freezerovernight. The insoluble phenethylamine salt is collected by vacuumfiltration and rinsed with 75 mL of fresh cold diethyl ether to afford72.0 g (80.5% yield over two steps-Example 1, Method 1 and Example 2,Method 1, 94.7% pure by HPLC) of the title compounds (25a′) as a whitesolid.

[0108] Method 2:

[0109] To a solution of the4-[4-(1-methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acid andof 4-[3-(1 -methoxycarbonyl-1 -methyl-ethyl)-phenyl]-4-oxo-butyric acid(25) from Example 1, Method 2 (22.0 g, 0.079 moles, 1.0 eq) in 100 mL ofdiethyl ether was added phenylethyl amine (10.5 g, 10.9 mL, 0.087 moles,1.1 eq.). The insoluble phenethylamine salt is collected by vacuumfiltration and rinsed with 25 mL of fresh diethyl ether to afford 30.0 g(95%) yield of the mixed isomer phenethylamine salts (25a′).

EXAMPLE 3 Scheme B. step b2: Preparation of4-[4-(1-Methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acidphenethylamine salt (VIIIa′)

[0110] Method 1:

[0111] The mixture of4-[4-(1-methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acidphenethylamine salt and of4-[3-(1-methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acidphenethylamine salt (25a′) obtained from Example 2, Method 1, (71.0 g)was crystallized from 2.1 L of hot isopropyl alcohol and collected byvacuum filtration to yield 36.9 g (52% yield) of a 91:9 (para:meta)isomeric mixture. The collected solid (36.9 g) was recrystallized from1100 mL of hot isopropyl alcohol and collected by vacuum filtration toyield 30.0 g (81.3% yield, 42.3% overall yield based upon the originalmixture, 70.4% total recovery of the para isomer) of4-[4-(methoxycarbonyl-1-methyl-ethy)-phenyl]4-oxo-butyric acidphenethylamine salt (VIIIa′). (Note: For maximum yield and speed ofcrystallization, it is recommended that the solution is seeded with purematerial after cooling to ambient temperature and then stored at −10°C.).

[0112] Method 2:

[0113] The mixture of4-[4-(1-methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acidphenethylamine salt and of4-[3-(1-methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acidphenethylamine salt (25a′) obtained from Example 2, Method 2 (30.0 g)was crystallized from 1 liter of hot isopropyl alcohol and collected byvacuum filtration to yield 12.8 g (43% yield) of an 85:15 (para:meta)isomeric mixture. The collected solid (12.8 g) was recrystallized from375 mL of hot isopropyl alcohol and collected by vacuum filtration toyield 10.2 g (80% yield, 34% overall yield based upon the originalmixture) of the title compound (VIIIa′).

EXAMPLE 4 Scheme B. Step b3: Preparation of4-[4-(1-Methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyric acid(VIII)

[0114] Method 1:

[0115] The 4-[4-(1-methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyricacid phenethylamine salt (VIIIa′) obtained from Example 3, Method 1(30.0 g) was dissolved in 800 mL of warm water and acidified withconcentrated hydrochloric acid to pH2. The aqueous layer was extractedwith ethyl acetate (2×300 mL). The organics were washed with water(1×100 mL), brine (1×100 mL), dried over MgSO₄, filtered andconcentrated in vacuo to 20.5 g (98.1% yield for conversion to the freeacid) of the title compound (VIII) as a white crystalline solid (99.8%pure by HPLC). (Note: It is not necessary to isolate the salt as inExample 1. The crude oil from Example 1 can be dissolved into isopropylalcohol directly, followed by the addition of phenethylamine.Crystallization occurs at −10° C., with a small reduction in overallyield.) MH⁺279.2.

[0116] Method 2:

[0117] The 4-[4-(1-methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyricacid phenethylamine salt (VIIIa′) obtained from Example 3, Method 2(10.2 g) was dissolved in 200 mL of warm water and acidified withconcentrated hydrochloric acid to pH2. The aqueous was extracted withethyl acetate (2×150 mL). The organics were washed with water (1×50 mL),brine (1×50 mL), dried over MgSO4, filtered and concentrated in vacuo togive 6.8 g (96% yield) of the title compound (VIII) was a clear oilwhich solidified upon standing.

EXAMPLE 5 Scheme B. step c: Preparation of2-(4-{4-4-(Hydroxy-diphenyl-methyl)-piperidine-1-yl-]-4-oxo-butyryl}-phenyl)-2-methyl-propionicacid methyl ester (IX)

[0118] Method 1:

[0119] The 4-[4-(1-Methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyricacid (VIII) (20.0 g, 0.0719 mole) obtained from Example 4, Method 1 wasdissolved in 250 mL of anhydrous tetrahydrofuran to which was addedtriethylamine (7.28 g, 10.02 mL, 0.0719 moles) in one portion. The flaskcontaining the solution was placed in an ambient temperature water bath.To the solution was added ethyl chloroformate (7.02 g, 6.19 mL, 0.0647mole) in THF (60 mL) dropwise over 1 minute. After addition, the mixturewas allowed to stir at ambient temperature for 15 minutes. To themixture was added α,α-diphenyl-4-piperidinomethanol (23) (19.2 g, 0.0719moles) in THF (120 mL) over 2 minutes. The mixture was stirred atambient temperature for 30 minutes. The solvent was removed under vacuumand the residue taken up in 600 mL of ethyl acetate. The organics werewashed with water (1×200 mL), dilute acid (1×200 mL), ¼ saturatedpotassium carbonate (2×200 mL), water (1×200 mL), brine (1×200 mL),treated with MgSO₄, filtered, concentrated and dried under high vacuumto give the title compound (IX) as a white solid (29.2 g, 85.6% yield,98.2% pure by HPLC). MH⁺528.4.

[0120] Method 2:

[0121] The 4-[4-(1-Methoxycarbonyl-1-methyl-ethyl)-phenyl]-4-oxo-butyricacid (VIII) (20.0 g, 0.0719 mole) obtained from Example 4, Method 2 (6.8g, 0.024 moles) and para-nitrophenol (6.7 g, 0.048 moles) was dissolvedin ethyl acetate (300 mL) and cooled to 0° C. in an ice-bath.1,3-Dicyclohexylcarbodiimide (9.9 g, 0.048 moles) was added to thechilled solution in one portion. The mixture is stirred at 0° C. for 1hour and then allowed to warm to ambient temperature where the mixtureis stirred for 7 hours. After than time azacyclonol (23) (7.1 g, 0.026moles) is added to the mixture in one portion. The mixture is allowed tostir overnight for 15 hours. The reaction mixture is filtered throughWhatman 541 paper to remove the precipitated 1,3-dicyclohexylurea. Thefiltrate is washed with ¼ saturated K2CO3 (3×100 mL), water (2×100 mL),dilute acid (1×100 mL), water (1×75 mL), brine (1×100 mL) and treatedwith MgSO4, filtered and concentrated to a yellow oil (10.9 g, 86%yield). The product is of sufficient purity to carry forward or ifdesired, a more pure sample can be obtained by crystallization fromacetonitrile (6 ml/gram with ˜80% recovery)

EXAMPLE 6 Scheme B. step d: Preparation of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid methyl ester (24)

[0122] Method 1:

[0123] The2-(4{-4-4-(Hydroxy-diphenyl-methyl)-piperidine-1-yl]-4-oxo-butyryl}-phenyl)-2-methyl-propionicacid methyl ester (IX) obtained from Example 5, Method 1 (28.0 g, 0.0531mole) was dissolved in 300 mL of dry THF. To the stirred solution wasadded borane-methyl sulfide complex (0.136 moles, 12.92 mL) dropwiseover five minutes. The mixture was heated at reflux for 60 minutes andthen cooled to ambient temperature over 15 minutes. Methanol (200 mL)was added (initial 50 mL dropwise) and the mixture was stirred for 30minutes. The mixture was concentrated under vacuum to give a whitesolid. The residue was dissolved in 300 mL of denatured ethanol andheated at reflux for 26 hours. The ethanol was removed in vacuo and thereaction product was taken up in ethyl acetate (1×500 mL). The organicswere washed with water (3×200 mL), brine (1×200 mL) and treated withMgSO₄, filtered and concentrated in vacuo to give 26.4 g (96.6%, 91.0%pure by HPLC) of the title compound (24) as a white solid. MH⁺516.6.

[0124] Method 2:

[0125] The2-(4-{4-4-(Hydroxy-diphenyl-methyl)-piperidine-1-yl]-4-oxo-butyryl}-phenyl)-2-methyl-propionicacid methyl ester (IX) obtained from Example 5, Method 2 (5.28 g, 0.01moles) was dissolved in 75 mL of dry THF. To the stirred solution wasadded borane-methyl sulfide complex (0.027 moles, 2.65 mL) dropwise overfive minutes. The mixture was heated at reflux for 45 minutes and thencooled to ambient temperature. Methanol (40 mL) was added (slowly atfirst) and the mixture was stirred for 30 minutes. The solvents wereremoved in vacuo to give a solid, which was dissolved in ethyl acetate(500 mL) and washed with water (1×200 mL). ¼ saturated K₂CO₃ (1×200 mL),water (1×200 mL), brine (1×200 mL), treated with MgSO₄, filtered andconcentrated in vacuo to a white solid. The white solid was dissolved in60 mL of methanol to which was added 30 mL of 37% formaldehyde. Themixture was refluxed for 18 hours. The methanol was removed in vacuo(alternatively the reaction can be diluted 5 fold with water as asubstitution of methanol removal) and the reaction product was extractedwith ethyl acetate (2×150 mL). The organics were washed with water(2×100 mL), brine (1×100 mL) and treated with MgSO₄, filtered andconcentrated in vacuo to give 4.7 g (91%) of the title compound (24) asa white solid of sufficient purity to carry forward.

EXAMPLE 7 Scheme B, step e: Preparation of 4-8 4-84-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,αdimethylbenzeneaceticacid (F)

[0126] Method 1:

[0127] The4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid methyl ester of Example 6, Method 1 (24) (20.0 g, 0.0388 mole) wasdissolved in 200 mL of methanol. To the solution was added a sodiumhydroxide solution (8.5 g in 85 mL water). The reaction mixture (cloudyat first then clears) was heated at reflux for 3 hours, and then cooledto ambient temperature. The solution was acidified to pH 4-5 with aceticacid (13.8 mL). The mixture was stirred at ambient temperature for 1.5hours. The precipitate was collected by vacuum filtration and driedunder vacuum to give 3.30 g (85% yield) of the title compoundFexofenadine (F) as a white solid. Purity assessment by HPLC 99.9%.Retention time and spectral match by HPLC against a fexofenadinestandard. MH⁺502.4

[0128] Method 2:

[0129] The4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid methyl ester of Example 6, Method 2 (4.0 g, 0.0078 moles) wasdissolved in 80 mL of methanol. To the solution was added a sodiumhydroxide solution (2.8 g in 24 mL of water). The reaction mixture washeated at reflux for 3 hours, and then cooled to ambient temperature.The solution was acidified to pH 4-5 with acetic acid, followed by theaddition of 40 mL of methanol. The mixture was stirred at ambienttemperature for 1.5 hours. The precipitate was collected by vacuumfiltration. The precipitate was dried under vacuum to give 3.3 g (85%)of the title compound fexofenadine (F) was a white solid. Purityassessment by HPLC 99.9%. Retention time and spectral match by HPLCagainst a fexofenadine standard. MH⁺502.4

EXAMPLE 8 Scheme A, optional step f: Preparation of4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneaceticacid methyl ester

[0130]4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid methyl ester (2.05 g, 0.00398 mol) was dissolved in 100 mL ofacetone and chilled in an ice-bath. To the solution was added Jonesreagent (Prepared via the method of Feiser and Feiser) dropwise until ared color persisted. The reaction was allowed to warm to roomtemperature and then stirred for 18 hours at ambient temperature. Themixture was concentrated under vacuum to give a green solid. The residuewas partitioned between ethyl acetate (150 mL) and water (150 mL). Theorganic layer was separated, washed with water (3×100 mL), brine (1×100mL) and treated with MgSO₄, filtered and concentrated in vacuo to give alight green solid. Purification via column chromatography yielded 1.25 g(61% yield) of the title compound as a white solid. MH⁺514.6.

1. The compound of the formula

wherein alkyl is 1-6 carbon atoms.
 2. The compound of claim 1 whereinalkyl is methyl.
 3. The compound of claim 1 wherein alkyl is ethyl. 4.The compound of the formula

wherein X⁺ is a Lewis acid and alkyl is 1-6 carbon atoms.
 5. Thecompound of claim 4 wherein X⁺ is


6. The compound of claim 5 wherein alkyl is methyl.
 7. The compound ofclaim 5 wherein alkyl is ethyl.
 8. The compound of the formula

wherein alkyl is 1-6 carbon atoms.
 9. The compound of claim 8 whereinalkyl is methyl.
 10. The compound of claim 8 wherein alkyl is ethyl. 11.The process for preparing a piperidine derivative compound of theformula

wherein alkyl is 1-6 carbon atoms comprising providing a compound of theformula:

wherein alkyl is 1-6 carbon atoms and converting the compound to thepiperidine derivative compound with a piperidine compound of theformula:


12. The process according to claim 11, wherein said providing comprises:a) acylating a starting compound of the formula:

wherein alkyl is 1-6 carbon atoms with a compound of the formula

under conditions effective to produce a mixture of regioisomers of theformula:

wherein alkyl is 1-6 carbon atoms; and b) recovering from the mixture ofregioisomers the compound of the formula:

wherein alkyl is 1-6 carbon atoms.
 13. The process according to claim 12wherein said recovering comprises crystallizing a regioisomeric salt ofthe formula:

wherein alkyl is 1-6 carbon atoms and X⁺ is a Lewis acid.
 14. Theprocess according to claim 13 wherein said recovering comprisescrystallizing a regioisomeric salt of the formula:

wherein alkyl is 1-6 carbon atoms.
 15. The process according to claim 12wherein alkyl is methyl.
 16. The process according to claim 12 whereinalkyl is ethyl.
 17. The process for preparing a compound of the formula

wherein R is COOH or COOalkyl and alkyl is 1-6 carbon atoms comprisingreducing a compound of the formula:


18. The process according to claim 17 wherein said reducing is carriedout using borane-methyl sulfide.
 19. The process for preparing apiperidine derivative compound of the formula

wherein alkyl is 1-6 carbon atoms comprising providing a compound of theformula:

wherein alkyl is 1-6 carbon atoms and converting the compound to thepiperidine derivative compound with a piperidine compound of theformula:


20. The process according to claim 19, wherein said providing comprises:a) acylating a starting compound of the formula:

wherein alkyl is 1-6 carbon atoms with a compound of the formula

under conditions effective to produce a mixture of regioisomers of theformula.

wherein alkyl is 1-6 carbon atoms; and b) recovering from the mixture ofregioisomers the compound of the formula:

wherein alkyl is 1-6 carbon atoms.
 21. The process according to claim 20wherein said recovering comprises crystallizing a regioisomeric salt ofthe formula:

wherein alkyl is 1-6 carbon atoms and X⁺ is a Lewis acid.
 22. Theprocess according to claim 21 wherein said recovering comprisescrystallizing a regioisomeric salt of the formula:

wherein alkyl is 1-6 carbon atoms.
 23. The process according to claim 19wherein alkyl is methyl.
 24. The process according to claim 19 whereinalkyl is ethyl.
 25. The process for preparing a compound of the formula

wherein alkyl is 1-6 carbon atoms comprising a) acylating a startingcompound of the formula:

wherein alkyl is 1-6 carbon atoms with a compound of the formula:

under conditions effective to produce a mixture of regioisomers of theformula:

wherein alkyl is 1-6 carbon atoms; and b) recovering from the mixture ofregioisomers the compound of the formula:

wherein alkyl is 1-6 carbon atoms; c) converting the compound of step b)to the piperidine derivative compound of the formula:

wherein alkyl is 1-6 carbon atoms with a piperidine compound of theformula:

d) reducing the piperidine derivative compound prepared in step c). 27.The process according to claim 26 wherein said reducing in step d) iscarried out using borane-methyl sulfide.
 28. The process according toclaim 26 wherein said recovering of step b) comprises crystallizing aregioisomeric salt of the formula:

wherein alkyl is 1-6 carbon atoms and X⁺ is a Lewis acid.
 29. Theprocess of claim 28 wherein said recovery of step b) comprisescrystallizing a regioisomeric salt of the formula:

wherein alkyl is 1-6 carbon atoms.
 30. The process of claim 26 whereinalkyl is methyl.
 31. The process of claim 26 wherein alkyl is ethyl. 32.The process for preparing a compound of the formula

comprising a) acylating a starting compound of the formula:

wherein alkyl is 1-6 carbon atoms with a compound of the formula:

under conditions effective to produce a mixture of regioisomers of theformula:

wherein alkyl is 1-6 carbon atoms; b) recovering from the mixture ofregioisomers the compound of the formula:

c) converting the compound of step b) to the piperidine derivativecompound of the formula:

wherein alkyl is 1-6 carbon atoms with a piperidine compound of theformula:

d) reducing the piperidine derivative compound of step c) to provide apiperidine derivative of the formula:

wherein alkyl is 1-6 carbon atoms; and e) converting the CO₂alkyl moietyto a CO₂H moiety.
 32. The process according to claim 31 wherein saidreducing in step d) is carried out using borane-methyl sulfide.
 33. Theprocess according to claim 32 wherein said recovering of step b)comprises crystallizing a regioisomeric salt of the formula:

wherein alkyl is 1-6 carbon atoms and X⁺ is a Lewis acid.
 34. Theprocess of claim 33 wherein said recovery of step b) comprisescrystallizing a regioisomeric salt of the formula:

wherein alkyl is 1-6 carbon atoms.
 35. The process of claim 30 whereinalkyl is methyl.
 36. The process of claim 29 wherein alkyl is ethyl.